Targeting inflammasomes as a therapeutic potential for HIV/AIDS

Abstract

Human immunodeficiency virus (HIV) infection in humans can cause a variety of symptoms. Among these, acquired immunodeficiency syndrome (AIDS) remains the most severe form. Current treatment of HIV/AIDS with antiretroviral drugs effectively inhibits HIV replication and infection and significantly extends the lifespan of HIV/AIDS patients. However, antiretroviral drugs cannot completely remove HIV from patients due to the high latency of HIV, and they possess side effects and can lead to drug resistance. HIV/AIDS remains to be an incurable disease, and new methods and drugs are still desirable. Inflammasomes were found to be activated during HIV infection and regulate AIDS progression. Previous reviews provide a simple summary of inflammasome activators and inhibitors during HIV infection without distinguishing the specific infection stage, this kind of summary does not provide any clinical target value. Here, we provide a comprehensive review of inflammasomes in HIV/AIDS according to the infection timeline and propose several inflammasome target strategies for clinical HIV/AIDS treatment. We systematacially summarized the activation and function of kinds inflammasomes during the different HIV infection stages, with the aim of providing new therapeutic targets and directions for HIV/AIDS and HIV-associated comorbidities.

Keywords: AIDS; CARD8; HIV; Inflammasome; NLRP3.

Fig. 1

Inflammasomes in acute HIV infection. Inflammasome activation during acute HIV infection. ① HIV infection generates ROS to activate the inflammasome. ② HIV infection causes extracellular ATP release from pannexin-1, which binds and activates P2Y2. Activated P2Y2 interacts with NLRP3 and recruits ubiquitin, leading to NLRP3 degradation and inflammasome inhibition. ③ HIV protein Gag interacts with IFI16 and inhibits inflammasome activation. ④ HIV Gag interacts with NLRP3 and inhibits inflammasome activation. ⑤ HIV protein Vpr interacts with caspase-1 and inhibits inflammasome activation. ⑥ HIV protein Vpu activates potassium ions channel Kv1.3 to activate the inflammasome. ⑦ CARD8 senses HIV^PR activity and assembly inflammasome. ⑧ NLRC4/NAIP recognize HIV protein gp41 and trigger inflammasome activation

Fig. 2

Inflammasomes in chronic and advanced HIV infection. A. Inflammasomes activation during chronic HIV infection. ①HIV abortive RNA activates PKR, which activates MAPK and generates ROS to provide both prime and activate signal for inflammasome. ②HIV ssRNA40 trigger NLRP3 inflammasome activation through a non-classical pathway requiring TLR8-Myd88, caspase-8. ③ART drug abacavir interacts with NLRP3 and triggers inflammasome activation.④ART drug nelfinavir interacts with AIM-2 and triggers inflammasome activation. B. Inflammasomes activated during advanced HIV infection, which induces pyroptosis and is responsible for CD4⁺ T cell loss

Fig. 3

Inflammasomes in HIV-associated comorbidities. ① HIV Vpr, Tat, and ssRNA40 prime and activate NLRP3 inflammasome; HIV gp120 activate NLRP1 and NLRP3 inflammasome; activated inflammasome contribute to HAND development. ② Inflammasomes including NLRC4/NAIP, NLRP1, NLRP3, and AIM-2 involved in HIV related cardiovascular disease attack. ③ SNPs of CARD8, NAIP/NLRC4 and NLRP3 impact HIV/TB co-infection progression. ④ NLRP3 inflammasome involved in other HIV-associated comorbidities

Fig. 4

Target inflammasomes for HIV cure. ① Target the prime process of inflammasomes. ② Target inflammasome activation signals.③ Target inflammasome effectors such as caspase-1, IL-1β, and IL-18. ④ Target inflammasome-induced cell death. ⑤ Activate inflammasomes for HIV treatment